The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion

Miller, Chaya; Wang, Liya; Østergaard, Elsebet; Dan, Phyllis; Saada, Ann

doi:10.1016/j.bbadis.2011.01.013

Cited by 48 publications

(53 citation statements)

References 18 publications

(20 reference statements)

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“…mtDNA depletion (15-40 % residual amount) was found in the muscle samples of such patients (Ostergaard 2008). However, mtDNA depletion was found in fibroblasts from patients with SUCLA2 deficiencies of only two out of four patients in one study (Carrozzo et al 2007), while in (Miller et al 2011) mtDNA depletion was evident only after serum deprivation which could be ameliorated by supplementation of deoxyribonucleosides. Data on brain biopsies from SUCLA2 deficiency patients are not available.…”

Section: Introductionmentioning

confidence: 91%

Exclusive neuronal expression of SUCLA2 in the human brain

et al. 2013

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SUCLA2 encodes the ATP-forming b subunit (A-SUCL-b) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here, we show that immunoreactivity of A-SUCL-b in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL-b immunoreactivity colocalized [99 % with that of the d subunit of the mitochondrial F 0 -F 1 ATP synthase. Specificity of the anti-A-SUCL-b antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL-b immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming b subunit (G-SUCL-b) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL-b immunoreactivity that was, however, not upregulated in samples obtained from diabetic versus nondiabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex.

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Section: Introductionmentioning

confidence: 91%

Exclusive neuronal expression of SUCLA2 in the human brain

et al. 2013

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“…For example, mutations in SUCLA2 and SUCLG1 leading to mtDNA depletion syndromes are thought to result from a nucleotide imbalance due to their role in generating ATP and GTP, rather than their function as subunits of the TCA cycle enzyme succinate-CoA ligase (42). Additionally, some of the genes implicated in mitochondrial RNA processing and modification (ELAC2, encoding RNase Z; PUS1, encoding pseudouridylate synthase 1; TRIT1, encoding tRNA isopentenyltransferase; TRNT1, encoding CCAadding tRNA nucleotidyl transferase) have been found to also function in the nucleus (43)(44)(45)(46).…”

Section: Genes With a Primary Role Specific To Oxphos Biogenesismentioning

confidence: 99%

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

Frazier

Thorburn

Compton

2019

Journal of Biological Chemistry

200

223

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Inherited disorders of oxidative phosphorylation cause the clinically and genetically heterogeneous diseases known as mitochondrial energy generation disorders, or mitochondrial diseases. Over the last three decades, mutations causing these disorders have been identified in almost 290 genes, but many patients still remain without a molecular diagnosis. Moreover, while knowledge of the genetic causes is continually expanding, understanding into how these defects lead to cellular dysfunction and organ pathology is still incomplete. Here, we review recent developments in disease gene discovery, functional characterization, and shared pathogenic parameters influencing disease pathology that offer promising avenues towards development of effective therapies.Mitochondrial energy generation disorders (hereafter termed mitochondrial diseases) are a heterogeneous group of rare disorders involving defective oxidative phosphorylation (OXPHOS). The OXPHOS system comprises five enzyme complexes, situated in the mitochondrial inner membrane. The first four complexes and two electron carriers form the respiratory chain, which generates a proton gradient used by complex V (F 1 F o ATP synthase) to generate the majority of cellular ATP. For the purpose of this review, we have focused on genes and mechanisms that have a demonstrated defect in primary energy generation (e.g. components of the OXPHOS system) or a clear expected role in mitochondrial homeostasis and the ability to generate energy (e.g. components of the TCA cycle and pyruvate dehydrogenase complex (PDC) that feed into OXPHOS, or those affecting mitochondrial membranes and structure).

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“…They are both mitochondrial matrix enzymes that catalyze the reversible synthesis of succinyl-CoA from succinate and CoA. The genes SUCLA2 and SUCLG2 tend to be highly expressed in anabolic and catabolic tissues, which suggests a function based on their tissue distribution [14]. In addition, we selected three genes known to encode propionyl Coenzyme A (PCCB), methylmalonyl CoA epimerase (MCEE), and methylmalonyl CoA mutase (MUT) respectively, which are involved in the essential process of conversion of propionyl-CoA to succinylCoA.…”

Section: Selection Of Candidate Genes and Snpsmentioning

confidence: 99%

Associations between gene polymorphisms in two crucial metabolic pathways and growth traits in pigs

Yang

Wang

et al. 2012

Chin. Sci. Bull.

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Propanoate metabolism and fatty acid metabolism are crucial metabolic pathways in vivo that have been studied extensively and have shown a significant influence on the growth and diseases of animals. In order to identify the essential genes significantly associated with porcine growth traits at the pathway level, we selected 14 candidate genes with 58 SNPs, including 24 tag SNPs and 34 predicted SNPs, in the two essential pathways to test using the SNaPshot mini-sequencing method. Association analysis was performed using both static and dynamic phenotypic records. The results showed that four SNPs, respectively in SUCLA2, SUCLG2, ACADS, and ALDH1B1, were significantly associated with growth in pigs. In addition, an exciting finding was that the change of transcription factor binding site that resulted from alteration of the bases in SUCLG2 brought out a transcription factor binding site for POU1F1a, which is the product of a notable marker gene for growth of animals. Growth traits, including total feed intake, daily feed intake, feed conversion ratio and daily weight gain, have a direct impact on production efficiency in the swine industry. Studies on the relationship between noted growth-related genes and growth traits have attracted a great deal of attention for decades. Unfortunately, despite the fact that numerous studies have been performed, few of them have demonstrated the nature and mechanism of genetic variation that underlies the quantitative traits. The methods for studying quantitative traits should be reconsidered, because the use of only SNPs as the basic units of association analysis has shown several limitations. The functions of SNPs and genes are usually carried out through intricate pathways of reactions and interactions [1]. Therefore, studies based on the candidate pathways approach may not only provide us with the possibility to gain more extensive insight into the functional basis of association but also facilitate and unravel the detailed genetic control mechanisms of complex phenotypes. Previous study in our laboratory has shown that the propanoate and fatty acid metabolic pathways exhibit significant down-regulation under PPARα knockout conditions in the livers of mice, which was detected by the analysis of mouse PPARα dependent or independent datasets by GSEA (Gene Set Enrichment Analysis) [2]. The propanoate and fatty acid metabolic processes are crucial metabolic pathways in vivo, and may be connected with the TCA (tricarboxylic acid cycle) cycle. Metabolism of fatty acids is essential for the organism because they are a major source of energy and the structural components of membranes. In addition, a variety of fatty acids perform key biological functions such as the regulation of lipid metabolism, cell division and inflammation [3][4][5]. The metabolism of propanoate (propionic acid) begins with its conversion to propionyl coenzyme A (propionyl-CoA), which is usually the first step in the metabolism of carboxylic acids. The regulatory mechanisms of the propanoate and fatty acid met...

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The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion

Cited by 48 publications

References 18 publications

Exclusive neuronal expression of SUCLA2 in the human brain

Exclusive neuronal expression of SUCLA2 in the human brain

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

Associations between gene polymorphisms in two crucial metabolic pathways and growth traits in pigs

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